Plasmodium berghei ANKA infection induces thymocyte apoptosis and thymocyte depletion in CBA mice

Abstract

Immune responses to malaria infections are characterized by strong T and B cell activation, which, in Key words: malaria -thymus -Plasmodium berghei -mice Malaria infections are characterized by defective immune responses, with poor efficacy and, in some cases, with the occurrence of immunopathology. The major lifethreatening malaria-related complications -cerebral malaria and severe anemia -have a strong immunological component in humans (Mackintosh et al. 2004) as well as in experimental models (De Souza & Riley 2002, Carvalho et al. 2003.The Plasmodium berghei ANKA infection in CBA mouse is an established model of malaria with neurological involvement (the so-called experimental cerebral malaria), and infection with blood stage parasites leads to 100% lethality. The immune response in this model is not only ineffective against parasite growth but also responsible for the 60-90% incidence of cerebral malaria (CM), mainly characterized by strong Th1 T cell responses (Hunt & Grau 2003), macrophage hyperactivation (Carvalho et al. 2000) and also CD8 + T cell cytotoxicity (Belnoue et al. 2002). T lymphocytes are central in CM pathogenesis. Early thymectomized CBA mice become resistant to CM development (Grau et al. 1986). Treatment of adult mice with anti-CD4 or anti-CD8 monoclonal antibodies also abrogate CM development, depending on the moment they are administered -early in infection for anti-CD4 and late in the infection for anti-CD8 (Grau et al. 1986 al. 2002). CM seems to be mediated by cells bearing αβ T cell receptors (TCR), since mice lacking T cells of the αβ lineage (TCR αβ -/-), but not of the γδ lineage (TCR γδ -/-), were resistant to CM development (Boubou et al. 1999). In addition, these authors showed that expression of CM was associated with an increase in T cells bearing the Vβ8.1 and Vβ8.2 segments, and CM expression was reduced in mice rendered deficient in cells bearing these segments.Although all the events concerning the participation of T cells in CM physiopathogenesis are related to peripheral responses, events occurring in the thymus cannot be disregarded. Indeed, infection by other protozoan parasites can potentially affect thymic function and then modulate T cell responses. In Trypanosoma cruzi infection in Balb/c mouse, intense thymic atrophy is reported, with loss of double positive immature thymocytes and appearance of such immature cells in secondary lymphoid organs (Mendes-da-Cruz et al. 2003). In addition, lymphocytes carrying normally forbidden TCR Vβ families are also exported from the thymus. According to these authors such cells could play a role in the autoimmune responses commonly observed during T. cruzi infections. Therefore, infection can affect thymic function resulting in pathological consequences or altering the efficacy of the immune response. In malaria, the consequences of malaria infection on thymus structure and function have been overlooked, with few works on the subject (Krettli & Nussenzweig 1974). In the present work, we evaluated the sequential histologica...

Characterization of cerebral malaria in the outbred Swiss Webster mouse infected by Plasmodium berghei ANKA

“…2003). Here we provide detailed description of the changes in these organs that were similar to changes observed in PbA‐inbred mouse models (Rest 1982; Carvalho et al. 2000, 2006, 2007).…”

“…2000) and on lymphoid organs, which act both as targets and as players in CM pathogenesis (Urban et al. 2005; Carvalho et al. 2006, 2007).…”

“…Histopathological analysis revealed cell death of thymocytes in the cortex (Figure 3e), varying from mild to intense, in some cases leading to thymocyte depletion. The intensity of cortical apoptosis, as previously described by Carvalho et al. (2006), could be divided in three patterns: (i) the cortex presented widespread foci of thymocyte death resulting in a ‘starry‐sky’ pattern of diffuse apoptosis with maintenance of cortical‐medullary structure; (ii) intense apoptosis with cortical atrophy, with absence of large cells – only small thymocytes could be seen; and (iii) severe cortical thymocyte depletion, resulting in cortical‐medullary inversion; only residual clusters of small thymocytes were observed within the framework of epithelial cells (Figure 3e).…”

Malaria Parasites: The Great Escape

“…This can result in apoptosis in monocytes, B cells, T cells, and DCs (194–199). Acute infection can also lead to thymus apoptosis and depletion, thereby diminishing the output of new naïve T cells (200). On the other hand, chronically activated T cells (both αβ and γδ) during lingering blood infection or multiple reinfections can also enter a phase of anergy (201–203) and/or exhaustion (204).…”

Germinal center architecture disturbance during Plasmodium berghei ANKA infection in CBA mice

“…Although immune responses to malaria and physiopathogenesis of cerebral malaria in mice have been widely studied [14-17], detailed analysis of changes in lymphoid compartments, which is basic to understand how the immune system respond to a challenge, has not been widely approached, with a few works mainly on the Plasmodium chabaudi model [18-20]. It has recently been shown that P. berghei ANKA-infected CBA mice develop various degrees of thymocyte apoptosis, leading in some cases to thymocyte depletion and severe thymus cortical atrophy [21]. In the present work, attention was focused on the sequential immunohistopathological changes caused by P. berghei ANKA infection in several lymphoid compartments and their possible implications in pathology and immunity of the infection.…”